Stable multiple X/O/Y-emulsion

ABSTRACT

The stable multiple emulsion of the X/O/Y type contains at least one X/O phase in which X is an oil-immiscible component and O an oil phase. The X/O phase can contains an active substance, possibly in solid form, for example for medical, cosmetic or technical applications. The Y phase can be an aqueous phase, an aqueous liquid, preferably liquid-crystalline, gel or a W/O/W emulsion and serves as carrier for the at least one X/O phase. The X/O phase is produced using an emulsifier that has an HLB value equal to or less than 6 and/or is a W/O emulsifier. The preparation of the X/O phase itself and its diffusion in the Y phase are done with standard stirring tools. The drops of the X/O phase have long-term stability and, even when greatly diluted, do not interact with the Y phase or the drops or other X/O phases dispersed therein.

This application is a 371 of PCT/EP94/03955 filed Nov. 29, 1994.

The present invention relates to a stable multiple emulsion of the X/O/Ytype.

Stable multiple emulsions of the W/O/W type are known, for example, fromGerman Published Patent Application No. 4,131,678 and are described in anumber of literature publications such as “Multiple Emulsions” by M.Frenkel et al. in J. Colloid Interface Sci., Vol. 94, pp. 174 to 178,1982; “The Formulation and Stability of Multiple Emulsions” by A. T.Florence et al. in Int. J. of Pharmaceutics, Vol. 11, pp. 277 to 308,1982; “Correlation between Nature of Emulsifier and Multiple EmulsionStability” by S. Magdassi et al. in Drug Development and IndustrialPharmacy, Vol. 11, pp. 791 to 798, 1985.

Accordingly a multiple emulsion generally consists of a W/O phase, i.e.a water-in-oil phase comprising drops of a hydrophilic liquid which aredispersed in a hydrophobic liquid, and an aqueous phase in which thesedrops are dispersed. The internal component of the W/O phase may beconstituted by, for example, an aqueous solution. The hydrophobicexternal component usually is selected from silicone oil, paraffin oil,triglyceride, fatty alcohol, ester oil or the like as well as mixturesthereof.

Such multiple emulsion can only be produced with the aid of emulsifiers.According to a generally acknowledged selection system, cf. Encyclopediaof Emulsion Technology, Ed. P. Becker, Marcel Dekker, New York, 1988,the emulsifiers are differentiated in accordance with an HLB value incorrespondence with the ratio of their hydrophilic and hydrophobicportions; the HLB value is the hydrophilic portion percentage, dividedby 5, of the emulsifier total molecular weight. Emulsifiers for formingW/O emulsions and having HLB values in the range of 3 to 6 aredistinguished from emulsifiers forming wetting agents and having HLBvalues in the range of 7 to 9 and from emulsifiers for forming O/Wemulsions and having HLB values in the range of 8 to 18.

In W/O/W emulsions of the initially mentioned type the aqueous phase isintended to serve as carrier for transporting the drops of the W/O phaseto their place of action in a manner such that the compound present inthe drops can not mix with or come into contact with the water.Important criteria therefore are the following:

1. Stability of the W/O phase against effects of temperature;

2. Stability of the W/O phase against coalescence;

3. Insensitivity to shearing forces occurring during preparation of theemulsion; and

4. Independence of the stability on the volume ratio of the W/O phaseand the aqueous phase.

Hitherto known multiple emulsions satisfy these requirements onlyimperfectly; up to now, improvements could only be achieved by requiringpassage through relatively complicated method steps when preparing theemulsion in order to be able to meet the desired stability requirements.Alternatively, specifically selected and composed emulsifiers had to beemployed in order to realize the desired stability. According to theinitially mentioned German Published Patent Application No. 4,131,678 amixture of emulsifiers is required, one of which is a W/O emulsifierhaving an HLB value in the range of far below 3 to close to 5 and another one of which has an HLB value in the range of 10 and far above.

Exclusively aqueous phases and oil phases were used in hitherto knownW/O/W emulsions. The use of non-aqueous phases therein has never beenconsidered.

In correspondence therewith it is the object of the invention to providea simply composed multiple emulsion which can be produced in simplemanner and which is significantly improved over known emulsions of theW/O/W type in terms of the afore noted stability criteria and itsutility.

In particular, the inventive stable multiple emulsion should permit theinclusion of solids.

In order to achieve these objects, the invention provides a stablemultiple emulsion of the X/O/Y type wherein X is a component immisciblewith oil, O is an oil phase and Y is an aqueous phase, and whichcontains an emulsifier selected from the group of emulsifiers having anHLB value of ≧6 and/or constituting a W/O emulsifier.

Advantageously, the emulsifier is selected from the group consisting ofglycerol esters, sorbitan esters, sorbitol esters, polyglycerol esters,fatty alcohols, propylene glycol esters, alkyl glucoside esters,carbohydrate esters, lecithin, silicone copolymers, their mixtures orderivatives.

The emulsions prepared with the aid of one of such emulsifiers areobtained by means of a simple mixing operation with stirring whereby thestability of such multiple emulsions is affected neither by the inputtedstirrer energy nor by the type of stirrer. In fact, any commerciallyavailable stirrer may be utilized for producing the inventive multipleemulsion.

The thus prepared multiple emulsions according to the invention possesslong-time stability and meet the usual stability requirements in thetemperature range of −5° C. to +45° C. The multiple emulsions accordingto the invention are stable in a highly water-diluted condition (1:100):Coalescence does not occur even after aggregation and creaming becausethe creamed material can be completely redispersed simply by shaking andthe thus restored emulsion again is just as stable as the originallyprepared emulsion.

The inventive stable multiple emulsions are particularly distinguishedby the fact that the drops contained therein have a size distributionbetween 1 μm and 10 μm and thus have a relatively small, in fact,smaller drop size than the known multiple emulsions which is ofconsiderable advantage for many applications.

In particular, however, according to the invention, it is possibledispersing a number of X/O phases separately from each other in theaqueous phase and therein long-time stability is given in the sense asnoted hereinbefore. The drops of the different X/O phases will remaincompletely separated from each other and there does not occur anyintermixing, exchange or the like with the external aqueous phase. Thisis of specific significance in all cases in which the X/O phases containdifferent active ingredients which are intended to be administeredseparately but in a common carrier in, for instance, medical or cosmeticapplications.

For this purpose, the Y phase or aqueous phase preferably constitutes anaqueous liquid, an aqueous gel or a multiple W/O/W emulsion. In thelatter case there is thus achieved the advantage that the W/O/W emulsioncan be mixed with one or more X/O emulsions in almost any desired volumeratio without loss in stability which can not be achieved or only to alimited extent when using pure water.

BRIEF DESCRIPTION OF DRAWINGS

The file of this patent contains at least one drawing executed in color.Copies of this patent with color drawing(s) will be provided by thePatent and Trademark Office upon request and payment of the necessaryfee.

FIG. 1 (reproduction 1) shows the X/o/Y emulsion in phase contrast at600-fold magnification.

FIG. 2 (reproduction 2) shows the same microphotograph taken withpolarized light.

Some inventive stable multiple emulsions will be described hereinbelowmerely as a matter of example for more detailed explanation of theinvention. All of the percentage data given therein for the variouscomponents are percent by weight of the total weight of the multipleemulsion=100. Given trivial names are taken from the CTFA index.

EXAMPLE 1

Using conventional vessels and stirrers, an oil phase and a water phasewere prepared and heated to a mixing temperature in the range of 20° C.to 90° C., preferably 60° C. to 80° C. Thereafter, the heated oil phaseand the heated water phase were combined with stirring by means of aconventional stirrer; after the combination, stirring is continued for afurther minute. The thus obtained emulsion subsequently is cooled orleft to cool to room temperature.

The oil phase contained: sorbitan monostearate  6.30%laurylmethicon-copolyol  2.70% paraffin oil 10.00% The water phasecontained demineralized water 80.80% phenonip  0.20%

In the following examples this emulsion will be designated as primaryemulsion; the emulsion constitutes a multiple W/O/W emulsion and servesfor preparing emulsions containing different X/O phases.

EXAMPLE 2

The multiple emulsion was prepared as described in Example 1; only thecomposition was different.

The oil phase contained sorbitan monostearate  4.50%laurylmethicon-copolyol  4.50% paraffin oil 10.00% cyclomethicon 10.00%The water phase contained demineralized water 70.80% phenonip  0.20%

EXAMPLE 3

This Example was intended to demonstrate the immiscibility of differentX/O phases by microscopic observation, the correspondingmicrophotographs being presented hereinbelow. This Examplesimultaneously also substantiates that finely divided solids liketitanium dioxide can be dispersed in one of the emulsions and may serveas light protective filter in cosmetic preparations.

A secondary emulsion No. 1 was composed of an oil phase and a waterphase.

The oil phase contained laurylmethicon-copolyol  1.5% paraffin oil 16.0%TIOVEIL MOTG  10.0%; (titanium dioxide dispersed in mineraloil/triglyceride) The water phase contained water 71.5% sodium chloride 1.0%

this secondary emulsion forms a W/O emulsion.

A secondary emulsion No. 2 contained an oil phase and an X component,namely

cyclomethicon + dimethicon-copolyol 15% cyclomethicon (oil phase) 30%and propylene glycol (X component) 55%

and thus forms an X/O emulsion.

The desired X/O/W emulsion, then, is obtained by heating the primaryemulsion of Example 1 to a temperature in the range of 20° C. to 90° C.,preferably 50° C. to 60° C.; thereafter, the secondary emulsions No. 1and No. 2 are added one after the other with stirring and the mixture iscooled to room temperature.

The primary emulsion of Example 1 and the secondary emulsion No. 1 arecombined in corresponding manner. After cooling to room temperature,samples are examined under a microscope; in the following reproductionsof the microphotographs it will be clearly recognized that the drops ofthe primary emulsion and the secondary emulsion are present separatelyand side by side. This structure remains preserved even after long-timestorage; even after aggregation and creaming followed by redispersion nochange will be recognized.

The reproduction 1 shows the X/O/Y emulsion in phase contrast at600-fold magnification. There will be recognized therein a large drop ofthe oil phase associated with the secondary emulsion No. 1 andsurrounded by a water phase consisting of the water phase of the primaryemulsion. The unstructured droplets of the water phase of the secondaryemulsion No. 1 will be recognized within the large drop. Theseunstructured droplets are present within the oil phase associated withthe secondary emulsion No. 1 and containing the titanium dioxide. Smalloil drops are located outside of the large oil drop and formed by theoil phase of the primary W/O/W emulsion; small water drops are dispersedtherein end will be recognized in the form of dark points. The two typesof oil drops are clearly present separately and side by side and, aswill be seen, the two oil phases do not mix with each other.

Reproduction 2 shows the same microphotograph taken with polarizedlight. Under these conditions the unstructured drops of the water phaseassociated with the primary emulsion appear dark whereas the titaniumdioxide particles in the oil drop of the secondary emulsion No. 1 appeardistinctly. The small oil drops located outside of the large oil dropappear only a little structured and are free of titanium dioxideparticles; they will be recognized thereby as oil drops of the primaryemulsion, water drops being only indistinctly visible within these oildrops.

The same results are obtained when the emulsifierlauryl-methicon-copolyol in the secondary emulsion No. 1 and/or theemulsifier dimethicon-copolyol in the secondary emulsion No. 2 isreplaced by any other emulsifier of the group of emulsifiers mentionedhereinabove on page 3.

EXAMPLE 4

This Example is intended to demonstrate that the multiple emulsions canbe present not only in liquid form but also as a gel.

Therefore, a liquid-crystalline gel is first prepared from a gel-formingemulsifier phase and a water phase. The emulsifier phase and the waterphase are separately heated to 80° C. Thereafter, the emulsifier phaseis added with stirring to the water phase and the mixture is cooled toroom temperature with continued stirring.

The gel phase contained methylglucoside stearate 10.0% water 89.8%phenonip  0.2%

The thus obtained liquid-crystalline gel is heated to a temperature inthe range of 20° C. to 90° C., preferably in the range of 50° C. to 60°C. and mixed with the secondary emulsions No.1 and No. 2 of Example 3one after the other with stirring. The components were used in thefollowing amounts, each in percent by weight of the total product=100:

liquid-crystalline gel 70% secondary emulsion No. 1 20% secondaryemulsion No. 2 10%

EXAMPLE 5

The liquid-crystalline phase obtained as in Example 4, is heated to atemperature in the range of 20° C. to 90° C., preferably 40° C. to 60°C.; thereafter, the secondary emulsions No. 1 and No. 2 of Example 3 andthe primary emulsion of Example 1 are added one after the other to theheated liquid-crystalline gel with stirring, particularly in the amountsas given hereinbelow in percent by weight of the total product=100:

liquid-crystalline phase 80% secondary emulsion No. 1 10% secondaryemulsion No. 2  5% primary emulsion  5%

The aforementioned stable multiple emulsions are particularly suited ascarriers for many types of active agents due to their stability and dueto the stability of the drops contained therein, whereby the carrier mayconstitute an aqueous liquid as well as a liquid-crystalline gel or aprimary emulsion of the W/O/W type in accordance with the Examples. Inthe following, it may be mentioned as a simple application example thatit is desirable having present the washing agent for a washing machinein liquid form because liquid washing agents can be more readily meteredthan solid washing agents. Furthermore, it is desirable to add enzymeslike proteases, lipases and amylases to the washing agent. Usually,however, such enzymes are not stable for long times in aqueous solution.The emulsion according to Example 3 offers a solution for the problem ofproviding a liquid enzyme-containing washing agent:

In this case the X/O phase is composed in correspondence with thesecondary emulsion No.2 whereby the enzyme is dissolved in the polyolphase wherein the enzyme is stable for long times. When the thus formedX/O phase is dispersed in water conjointly with detergents, there isobtained a liquid washing agent wherein the enzyme is separated from theaqueous phase due to the fact that the interior of the drops, i.e. thepolyol solution of the enzyme, is protected from contact and exchangewith the aqueous phase by means of the emulsifier. The enzyme can bereleased only upon destruction of the emulsifier. In accordance with theselection of the emulsifier this can be achieved immediately at thestart of the washing operation by breaking the emulsion either due tothe prevailing temperature or due to the combined effects of thetemperature and the shearing forces occurring during the washingoperation.

The preparation of emulsions containing different X/O phases alsopermits placing mutually incompatible active agents into a common singlecarrier. In the field of cosmetics, for example, it is frequentlydesirable to apply to the skin mutually incompatible active agents likecollagen preparations and urea. This is impossible under standardconditions, when using an aqueous carrier gel. Specifically, under suchconditions, the collagen preparation would become denatured in theaqueous phase by the urea whereby it would be rendered ineffective, see“Kollagen in der Kosmetik” by H. Lindner in Parfumerie und Kosmetik,Vol. 65, pp.340-343; 1984. However, when the two active agents areseparately applied to the skin, such denaturation will not ensue. Thiscan be achieved by using an emulsion in correspondence with Example 4:

Both the active agents are dispersed in a common carrier gel under theseconditions, the emulsifier again preventing the ingredients of the X/Ophases from contacting or interacting with each other or with thecarrier gel. In correspondence with Example 4, a carrier gel having aliquid-crystalline base is prepared; a secondary emulsion No. 1 isobtained in correspondence with Example 3 by dissolving urea instead ofsodium chloride in the water phase and by dispensing with the titaniumdioxide dispersion in the oil phase; in correspondence with thesecondary emulsion No. 2 of Example 3, the collagen preparation isdissolved in the polyol phase which is, then, dispersed in therespective oil phase. The carrier gel, which is prepared according toExample 4, then, contains the two active agents in the oil dropsassociated with the different X/O phases and separated from each otherin the absence of mutual exchange or exchange with the aqueous carriergel so that the total product is stable for long times. When applied tothe skin the emulsion will be broken, however, the two active agents areresorbed by the skin in different manner and at a rate such thatdenaturation of the collagen preparation does not occur despite thecommon application.

In corresponding manner also drugs which are effective at differentlocations, can be dispersed in different X/O phases which, in turn, canbe dispersed in a common carrier as described in Example 3. It is thuspossible to place into a common liquid carrier, for example,pharmaceutical agents which are intended to become effective atdifferent locations of the digestive tract. This is achieved by usingdifferent emulsifiers for preparing the respective X/O phases whichemulsifiers are unstable under conditions prevailing at the respectivelocations of action. The active agents present in the drops of the X/Ophases, are then released thereby.

For instance, there can be prepared a first X/O phase wherein theoil-immiscible component constitutes an aqueous solution of an activeagent and the used emulsifier is an emulsifier which rapidly hydrolyzesin an acid medium. Furthermore, a second X/O phase corresponding to thesecondary emulsion No. 2 according to Example 3 is obtained whereby theemployed emulsifier is an acid-stable emulsifier such as a siliconecopolymer. Both the X/O phases are dispersed in water which forms thecarrier liquid. After oral administration, the emulsifier present in thefirst X/O phase is hydrolyzed under the action of gastric acid so thatthe active agent present in this X/O phase will be released in thestomach. The emulsifier present in the second X/O phase is stable underthese conditions so that the second X/O phase passes unchanged throughthe stomach. Much more, the respective active agent will only bereleased thereafter in the digestive tract, namely in a section wherethe emulsifier is degraded or dissolved. The selection of emulsifierscan be readily adapted to the conditions prevailing at the locations ofaction.

The oil phase and/or the X component may contain solids such aspigments, microspheres, silica gel or wax. Pigments may serve as lightprotective filters (for instance, in the field of cosmetics),microspheres or silica gel may be utilized as carriers for activeagents, and wax can be used as a base of, for example, a polish.

It will be self-evident that, during preparation of emulsions containingactive agents of the aforementioned type, it will be readily possible toadd to the emulsions, apart from the active agents as such, all otheradjuvants and additives as required for the respective purpose of use.

What is claimed is:
 1. Stable multiple emulsion of the X/O/Y type inwhich X constitutes a component immiscible with oil and O is an oilphase and Y an aqueous phase and which contains at least one emulsifierselected from the group consisting of emulsifiers having an HLB value≦6and/or a W/O emulsifier with the proviso that no water-solubleemulsifier is present in the aqueous phase when a W/O emulsion isdispersed therein.
 2. Stable multiple emulsion according to claim 1,characterized in that the aqueous phase constitutes an aqueous liquid,an aqueous gel or a multiple W/O/W emulsion.
 3. Stable multiple emulsionaccording to claim 2, characterized in that the gel is formed using anemulsifier forming a liquid-crystalline network.
 4. Stable multipleemulsion according to claim 1, characterized in that the emulsifier isselected from the group consisting of glycerol esters, sorbitan esters,sorbitol esters, polyglycerol esters, fatty alcohols, propylene glycolesters, alkyl glucoside esters, carbohydrate esters, lecithin, siliconecopolymers and their mixtures.
 5. Stable multiple emulsion according toclaim 4, characterized in that the esters are formed of long-chainsaturated fatty acids or a mixture of long-chain saturated andunsaturated fatty acids which mixture is solid at room temperature. 6.Stable multiple emulsion according to claim 1, characterized in that theoil phase is selected from the group consisting of silicone oils,paraffin oils, triglycerides, fatty alcohols, ester oils and mixturesthereof.
 7. Stable multiple emulsion according to claim 6, characterizedin that the oil phase contains a solid selected from the groupconsisting of pigments, microspheres, silica gel, and wax.
 8. Stablemultiple emulsion according to claim 1, characterized in that the Xcomponent constitutes a polyol miscible with water.
 9. Stable multipleemulsion according to claim 8, characterized in that the polyol isselected from the group consisting of propylene glycol, butylene glycol,polyalkylene glycol, glycerol, polyglycerol and mixtures thereof. 10.Stable multiple emulsion according to claim 8, characterized in that theX component contains an active agent selected from the group consistingof pharmaceutical agents, cosmetic agents, and agents relating towashing, food or agricultural technology.
 11. Stable multiple emulsionaccording to claim 8, characterized in that the X component contains asolid selected from the group consisting of pigments, microspheres,silica gel, and wax.
 12. Stable multiple emulsion according to claim 1,characterized in that a number of X components are provided anddispersed in respective oil phases, the thus formed different X/O phasesbeing present in the X/O/Y emulsion side by side and permanentlyseparated from each other.
 13. Stable multiple emulsion according to anyone of the preceding claims, characterized in that the X/O phase isformed of drops having a diameter in the range of 1 μm to 10 μm. 14.Method of preparing a stable multiple emulsion of the X/O/Y type inwhich X is a component immiscible with oil, O is an oil phase and Y anaqueous phase and which contains at least one emulsifier, wherein theemulsifier is selected from the group consisting of emulsifiers havingan HLB value≦6 and/or a W/O emulsifier, with the proviso that nowater-soluble emulsifier is present in the aqueous phase when a W/Oemulsion is dispersed therein comprising the steps of mixing an X/Ophase and the aqueous phase, said phases being preheated to 20° C. to90° C. before mixing; and cooling the mixture to room temperature. 15.Method according to claim 14, characterized in that the X/O phase andthe aqueous phase are separately heated to a temperature in the range of60° C. to 80° C.
 16. Method according to claim 14, characterized in thatthe aqueous phase is selected from the group consisting of an aqueousliquid, an aqueous gel and a multiple W/O/W emulsion.
 17. Methodaccording to claim 16, characterized in that the gel is formed by usingan emulsifier which forms a liquid-crystalline network.
 18. Methodaccording to claim 14; characterized in that a first X/O/Y emulsion isheated to a temperature in the range of 20° C. to 90° C. and mixed withstirring with a second X/O/Y emulsion which has been prepared in thesame manner, and that the mixture is cooled to room temperature. 19.Method according to claim 18, characterized in that the first X/O/Yemulsion is heated to a temperature in the range of 50° C. to 60° C. 20.Method for preparing a stable multiple emulsion of claim 14 in which theX/O phase contains a pharmaceutical agent, a cosmetic agent or an activeagent relating to the washing, food or agricultural technology. 21.Method for preparing a stable multiple emulsion of claim 14 wherein thestable multiple emulsion contains a number of X/O phases which arepresent side by side separately from each other.
 22. Method of claim 21,characterized in that the number of X/O phases, which are present sideby side separately from each other, contain respective active agentswhich differ from each other.
 23. Method according to claim 14,characterized in that the emulsifier is selected from the groupconsisting of glycerol esters, sorbitan esters, sorbitol esters,polyglycerol esters, fatty alcohols, propylene glycol esters, alkylglucoside esters, carbohydrate esters, lecithin, silicone copolymers andtheir mixtures.
 24. Method according to claim 23, characterized in thatthe esters are formed of long-chain saturated fatty acids or a mixtureof long-chain saturated and unsaturated fatty acids which mixture issolid at room temperature.
 25. Method according to claim 14,characterized in that the oil phase is selected from the groupconsisting of silicone oils, paraffin oils, triglycerides, fattyalcohols, ester oils and mixture thereof.
 26. Method according to claim25, characterized in that the oil phase contains a solid selected fromthe group consisting of pigments, microspheres, silica gel, and wax. 27.Method according to claim 14, characterized in that the X componentconstitutes a polyol miscible with water.
 28. Method according to claim27, characterized in that the polyol is selected from the groupconsisting of propylene glycol, butylene glycol, polyalkylene glycol,glycerol, polyglycerol and mixtures thereof.
 29. Method according toclaim 27, characterized in that an active agent is added to the Xcomponent and selected from the group consisting of pharmaceuticalagents, cosmetic agents and active agents relating to washing, food oragricultural technology.
 30. Method according to claim 27, characterizedin that the X component contains a solid selected from the groupconsisting of pigments, microspheres, silica gel, and wax.
 31. Methodaccording to claim 14, characterized in that the X/O phase is dispersedto form drops having a diameter in the range of 1 μm to 10 μm.